PROJECT SUMMARY: Our prior work demonstrated hypothesis-driven characterizations of the phenotypes associated with frontotemporal lobar degeneration (FTLD), including progressive non-fluent aphasia (PNFA), semantic dementia (SD), and behavioral variant patients with a social and executive disorder (bvFTD). We also began to relate these syndromes to the major pathologies underlying FTLD. However, little work has determined the value of clinical features for predicting pathology. We propose novel studies that optimize features we can use to characterize PNFA, SD and bvFTD. We will obtain converging evidence for these observations from novel MRI techniques integrating grey matter (GM) atrophy and white matter (WM) tract defects, and from functional MRI (fMRI) studies of healthy adults using the same materials. Finally, we will relate FTLD phenotypes to pathology, and determine how these associations are modulated by genetic factors. Aim 1 addresses the basis for non-fluent speech in PNFA. We propose studies of conversational discourse in PNFA to highlight the combined role of grammatical and executive deficits in their language disorder. Integrated GM-WM imaging will relate this to left frontal disease, and converging evidence for an fMRI study of healthy adults will confirm this. Aim 2 will examine the role of degraded perceptual feature knowledge in the semantic deficit of SD patients. Imaging studies will, relate poor knowledge of visual object features to visual association cortex in the ventral temporal lobe and poor auditory feature knowledge to dorsal temporal regions. An fMRI study in healthy adults will provide converging evidence for the anatomic relationships of visual and auditory feature knowledge of object concepts. Aim 3 will demonstrate the role executive limitations in the most devastating social disorders of bvFTD patients. We will identify two forms of apathy - a vegetative form manifested as poor motivation, and an executive form that relates apathy to difficulty with multi-step tasks. Using integrated GM-WM imaging, we expect these two forms of apathy to be associated with disease in different frontal regions. Different forms of disinhibition also will be identified. One form will be related in part to impoverished social knowledge and right temporal disease, and a second form related to executive dysfunction (e.g. mental switching difficulty) involving right ventral prefrontal disease. Aim 4 will test the hypothesis that non-fluent speech due to grammatical difficulty in PNFA is associated with FTLD-Tau, and this association will be strengthened by tau haplotype. Degraded feature knowledge for object concepts in SD will be associated with FTLD-TDP, and this will be strengthened by TMEM106B. We will also test the hypothesis that the vegetative form of apathy in bvFTD is related to FTLD-Tau, while disinhibition due to impaired social knowledge is related to FTLD-TDP. This work will advance cognitive neuroscience in the areas of language processing, semantic memory, and social cognition. These findings will contribute crucially to diagnostic accuracy, clarify specific clinical features that are most likely to refiect underlying pathology, and provide meaningful endpoints for treatment trials.